Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

FMR1 前突变母携带者的衰老症状轨迹

• 批准号: 10445687
• 负责人: Jessica Klusek
• 金额: $ 60.67万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445687
• 关键词: Activities of Daily Living; Adopted; Adult; Advocate; Affect; Age; Aging; Anxiety; Autoimmune; Autonomic Dysfunction; Autonomic nervous system; Biological; Biological Factors; Caring; Characteristics; Child; Child Rearing; Classification; Clinical; Clinical Management; Cross-Sectional Studies; DNA Sequence Alteration; Data; Development; Environmental Risk Factor; Executive Dysfunction; Eye; FMR1; FMR1 Premutation; FMRP; Family; Fragile X Syndrome; Functional disorder; Future; Gene Abnormality; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Glean; Goals; Growth; Heart Rate; High Prevalence; Impairment; Individual; Infertility; International; Investigation; Life; Long-Term Effects; Mental Depression; Mental Health; Messenger RNA; Modeling; Molecular Abnormality; Molecular Genetics; Mothers; Mutate; Neurodegenerative Disorders; Outcome; Parents; Partner in relationship; Phenotype; Physiological; Play; Premature Menopause; Prevention; Process; Public Health; Risk; Risk Factors; Role; Sinus Arrhythmia; Statistical Methods; Stress; Symptoms; Testing; Time; United States; Woman; Work; age related; aged; chronic painful condition; clinical risk; disability; disorder risk; executive function; experience; human old age (65+); improved; improved outcome; innovation; longitudinal design; men; middle age; premature; respiratory; social; social communication; social deficits; social skills; stressor

PROJECT SUMMARY/ABSTRACT About 1 in 151 women in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Mothers who carry the FXpm are at risk for passing the mutated gene to their children, which may result in fragile X syndrome. The FXpm is also associated with substantially increased risk for disease, including neurodegenerative disease, premature menopause, psychiatric involvement, and executive and social deficits. New evidence suggests that FXpm carrier mothers may experience premature age-related decline across multiple symptom domains. The aging expression of FXpm phenotype is particularly concerning when applied within the context of fragile X families because these symptoms impact not only the carrier mother, but also her ability to care and advocate for her children with fragile X syndrome. However, almost all evidence of age- related decline in this group has been gleaned from cross-sectional data that are insufficient for drawing robust longitudinal trajectories. This represents a substantial barrier to effective clinical management, as we lack the data needed to understand the long-term effects of the FXpm genotype and its implications for families. This proposal seeks to determine the stability of key FXpm phenotypes (mental health, executive, social) across midlife and early old age in FXpm carrier mothers compared to healthy controls (Aim 1); investigate autonomic and molecular-genetic factors associated with age-related symptom expression and their interface with parenting stress (Aim 2); and evaluate functional limitations associated with FXpm symptoms across age (Aim 3). We will accomplish these aims by adopting an accelerated longitudinal design to track age-related change occurring across 45-80 years in 75 FXpm carrier mothers compared to 75 control mothers. The over- arching goal is to inform the critical age periods and risk factors in age-related decline, as well as to lay the groundwork for future mechanistic studies. This work is necessary to develop strategies to ameliorate FXpm symptoms, which will improve outcomes for both FXpm carrier mothers and their children with fragile X syndrome.

项目总结/摘要 在美国，每151名女性中就有1名携带有一种称为FMR 1前突变的遗传异常。 （FXpm）.携带FXpm的母亲有将突变基因传给孩子的风险，这可能导致 脆性X染色体综合征FXpm还与疾病风险大幅增加相关，包括 神经退行性疾病、过早绝经、精神疾病以及执行和社交缺陷。 新的证据表明，FXpm携带者的母亲可能会经历过早的年龄相关的下降， 多个症状域。FXpm表型的衰老表达在应用时特别令人关注 因为这些症状不仅影响携带者母亲， 有能力照顾和倡导她患有脆性X综合征的孩子。然而，几乎所有的年龄证据- 从横截面数据中收集到的这一群体的相关下降不足以得出可靠的结论。 纵向轨迹这是有效临床管理的一个重大障碍，因为我们缺乏 数据需要了解FXpm基因型的长期影响及其对家庭的影响。 该提案旨在确定关键FXpm表型（心理健康，执行，社会）的稳定性 FXpm携带者母亲与健康对照组相比，在中年和老年早期（目标1）;研究 与年龄相关症状表达相关的自主和分子遗传因素及其界面 父母压力（目标2）;并评估与不同年龄段FXpm症状相关的功能限制 (Aim 3）。我们将通过采用加速纵向设计来跟踪与年龄相关的 与75名对照母亲相比，75名FXpm携带者母亲在45-80岁期间发生的变化。过度- 该研究的目的是告知年龄相关衰退的关键年龄段和风险因素，以及奠定 为今后的机制研究奠定基础。这项工作对于制定改善FXpm的策略是必要的 症状，这将改善FXpm携带者母亲及其患有脆性X的孩子的结果 综合征